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CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response.

ABSTRACT: The gene encoding the target of calcium channel blockers, the alpha1c-subunit of the L-type calcium channel (CACNA1C), has not been well characterized, and only small pharmacogenetic studies testing this gene have been published to date.Resequencing of CACNA1C was performed followed by a nested case-control study of the INternational VErapamil SR/trandolapril STudy (INVEST) GENEtic Substudy (INVEST-GENES). Of 46 polymorphisms identified, 8 were assessed in the INVEST-GENES. Rs1051375 was found to have a significant interaction with treatment strategy (P=0.0001). Rs1051375 A/A genotype was associated with a 46% reduction in the primary outcome among those randomized to verapamil SR treatment, when compared with atenolol treatment (odds ratio 0.54 95% CI 0.32 to 0.92). In heterozygous A/G individuals, there was no difference in the occurrence of the primary outcome when randomized to verapamil SR versus atenolol treatment (odds ratio 1.47 95% CI 0.86 to 2.53), whereas homozygous G/G individuals had a greater than 4-fold increased risk of the primary outcome with verapamil treatment compared with those randomized to atenolol treatment (odds ratio 4.59 95% CI 1.67 to 12.67). We did not identify allelic expression imbalance or differences in mRNA expression in heart tissue by rs1051375 genotype.Variation in CACNA1C is associated with treatment response among hypertensive patients with stable coronary artery disease. Our data suggest a genetically defined group of patients that benefit most from calcium channel blocker therapy, a group that benefits most from beta-blocker therapy, and a third group in which calcium channel blocker and beta-blocker therapy are equivalent.

SUBMITTER: Beitelshees AL

PROVIDER: S-EPMC2761685 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response.

Beitelshees Amber L AL Navare Hrishikesh H Wang Danxin D Gong Yan Y Wessel Jennifer J Moss James I JI Langaee Taimour Y TY Cooper-DeHoff Rhonda M RM Sadee Wolfgang W Pepine Carl J CJ Schork Nicolas J NJ Johnson Julie A JA

Circulation. Cardiovascular genetics 20090603 4

<h4>Background</h4>The gene encoding the target of calcium channel blockers, the alpha1c-subunit of the L-type calcium channel (CACNA1C), has not been well characterized, and only small pharmacogenetic studies testing this gene have been published to date.<h4>Methods and results</h4>Resequencing of CACNA1C was performed followed by a nested case-control study of the INternational VErapamil SR/trandolapril STudy (INVEST) GENEtic Substudy (INVEST-GENES). Of 46 polymorphisms identified, 8 were asse ...[more]

PMID: 20031608

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Project description:BackgroundPrevious studies have examined the associations between polymorphisms of adiponectin gene (ADIPOQ) and cardiovascular disease (CVD), but those studies have been inconclusive. The aim of this study was to access the relationship between three single nucleotide polymorphisms (SNPs), +45 T > G (rs2241766), +276 G > T (rs1501299) and -11377 C > G (rs266729) in ADIPOQ and CVD.MethodsA comprehensive search was conducted to identify all studies on the association of ADIPOQ gene polymorphisms with CVD risk. The fixed and random effect pooled measures (i.e. odds ratio (OR) and 95% confidence interval (CI)) were calculated in the meta-analysis. Heterogeneity among studies was evaluated using Q test and the I2. Publication bias was estimated using modified Egger's linear regression test.ResultsThirty-seven studies concerning the associations between the three polymorphisms of ADIPOQ gene and CVD risk were enrolled in this meta-analysis, including 6,398 cases and 10,829 controls for rs2241766, 8,392 cases and 18,730 controls for rs1501299 and 7,835 cases and 14,023 controls for rs266729. The three SNPs were significantly associated with CVD, yielding pooled ORs of 1.22 (95%CI: 1.07, 1.39; P = 0.004), 0.90 (95%CI: 0.83, 0.97; P = 0.007) and 1.09(95%CI: 1.01, 1.17; P = 0.032) for rs2241766, rs1501299 and rs266729, respectively. Rs2241766 and rs1501299 were significantly associated with coronary heart disease (CHD), yielding pooled ORs of 1.29 (95%CI: 1.09, 1.52; P = 0.004) and 0.89 (95%CI: 0.81, 0.99; P = 0.025), respectively. The pooled OR for rs266729 and CHD was 1.09 (95%CI: 0.99, 1.19; P = 0.090). Significant between-study heterogeneity was found in our meta-analysis. Evidence of publication bias was observed in the meta-analysis.ConclusionsThe present meta-analysis showed that the associations between rs2241766, rs1501299 and rs266729 in the ADIPOQ and CVD were significant but weak. High quality studies are still needed to confirm the associations, especially for rs2241766.

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CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response.

Publications

CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response.

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